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Chronic Neuroimmune Diseases
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Last updated January 1, 2014

The following is excerpted from the original 11 page article.

Introduction
MCS is a controversial disorder characterized by multi-organ symptoms in response to low-level chemical exposures that are considered safe for the general population. Individuals with MCS most often report that their symptoms are elicited by chemical exposures and certain foods, and that prior exposure to the same or a different chemical initiated their subsequent sensitivities. Evolutionary theory provides a model for the observation that animals optimize their chances for survival and reproduction using various physiological and behavioral strategies. Evolutionarily, these strategies provide for stability over succeeding generations. This theory has recently been adopted to help explain drug abuse (Newlin, submitted) as well as MCS (Newlin, 1999) in terms of motivation to inflate or to protect self-perceived survival ability and reproductive fitness (SPFit). SPFit is a proposed psychological construct (in humans) that reflects the internalization of survival and reproductive motivations.

As a first step toward testing some of the hypotheses put forth for MCS, we have developed an animal model of MCS in rats based upon three behavioral endpoints for which the underlying neural circuitry is relatively well described. This circuitry appears to mediate the motivational aspects of approach and avoidance responses to potentially life-threatening stimuli, and is therefore highly relevant to evolutionary theory.

Cross-Sensitization Hypothesis And Multiple Chemical Sensitivity
Bell, Miller and Schwartz (1992) first discussed the notion that the onset/maintenance of MCS is similar to neural sensitization observed in rodents. Neural sensitization, referred to here simply as "sensitization", is the amplification of behavioral and underlying neurochemical responses to a stimulus after repeated perturbation with either stressful stimuli or drugs of abuse such as amphetamine, cocaine, and morphine. The initiation phase of sensitization occurs during the period that animals are being exposed to the stimulus, which is most often given repeatedly over several days. At a later point in time, animals demonstrate an enhanced reactivity to that stimulus, referred to as the expression phase of sensitization. For example, a rat repeatedly administered cocaine will demonstrate an augmentation in locomotor activity to subsequent cocaine compared with an animal that receives repeated saline injections. Stressful stimuli, such as restraint, tail pinch or foot shock stress, given repeatedly also produce sensitized locomotor activity to a subsequent psychostimulant injection (referred to as "cross-sensitization"), and even a single episode of stress can produce enhanced responding to a later stimulus.

Like sensitization, the development of MCS has been described as a dual-phase process. The initiation phase is thought to be the stage during which either repeated exposure to chemicals or high-level chemical exposure (such as that occurring during a chemical spill) initiates the process of later sensitivity to chemicals. Thus, initiation events appear to set the individual on a course during which very low levels of subsequent encounters with chemicals or foods elicit the symptoms described above. The experience of symptoms is described as the elicitation phase; it is during this phase that individuals report extreme sensitivity to odors and feelings of illness from chemical exposures encountered at the home and workplace. Another term used for the elicitation phase is triggering.

Our studies have used a rat model to explore the notion that repeated chemical exposure may produce amplified responding (cross-sensitivity) to later presentation of chemicals. For the studies described below, formaldehyde (Form) was chosen for study because it is among the most ubiquitous volatile organic compounds found in indoor air, present in hundreds of common products, such as paper, insulation, wood products, and resins, and appears to produce illness in many humans with sensitivity to chemicals. It is an upper airway irritant in rodents as well, and our recent studies have indicated that Form exposure produces an elevation in basal corticosterone (CORT) levels when given repeatedly at low levels (0.7 ppm), and increased responsiveness to subsequent Form exposure in rats given repeated exposure to higher levels (2.4 ppm).

Relevant to altered activation of the CORT response regarding either basal levels or CORT levels after Form challenge is that such alterations can perturb normal CNS functioning. Chronic elevation of CORT levels has been linked to alterations in corticotropin-releasing hormone (CRH) in the central nucleus of the amygdala and bed nucleus of the stria terminalis. These brain regions have been implicated in fear and anxiety and may increase anticipatory angst in individuals. Increased fear and anxiety and altered cortisol levels in humans have been associated with clinical syndromes, such as PTSD and depression. Interestingly, both of these disorders have been associated with the profile of subpopulations of MCS patients. While fearful depressed patients exhibit increased basal plasma cortisol levels, recent studies in PTSD individuals indicate lower basal cortisol levels but enhanced reactivity of the HPA axis to subsequent stimuli in PTSD. Posttraumatic stress disorder is often described as a sensitization disorder, and it has been suggested that certain individuals may be predisposed to become sensitized to traumatic stressors. If there are similarities between MCS and PTSD, MCS may also be an endpoint reached by those predisposed to sensitization to environmental stimuli in the form of chemicals/foods.

Are MCS And Drug Abuse Polar Opposites?
Several investigators have proposed that MCS may be diametrically opposite to drug addiction in that the former represents movement away from chemicals, while drug addiction represents movement toward chemicals (drugs of abuse). The idea that MCS and drug abuse may have clinical features which oppose each other yet share genetic predisposition is supported by reports of significantly greater family history of drug abuse in individuals who consider themselves intolerant to chemicals. Significant increases in the rate of alcoholism in the blood relatives of MCS patients has also been recently reported.

One investigator has pointed out the possibility that those who seek out solvent intoxication may differ from those who become aversive to solvent odors in their individual sensitivities. For example, an anxiety response may be initiated in the MCS patient while, for unknown reasons, inhalant abusers may not activate these systems. In Trichloroethylene, a commonly abused inhalant, the chemical produces many of the same symptoms as MCS, such as headache, fatigue, irritability, depression, and alcohol intolerance, but individuals who abuse this inhalant nevertheless find the intoxicating effects pleasurable.

Fig. 1. Neural circuitry mediating approach/avoidance responses to environmental stimuli, individuals with MCS manifest extreme avoidance behavior, whereas in drug abusers, extreme approach behavior toward drugs of abuse is observed. Sensitization is represented by increased gain of the mesolimbic dopamine related circuitry and/or projections from the amygdala, hippocampus (hippo) or prefrontal cortex (PFC) after repeated exposure to environmental chemicals in MCS patients, and to drugs of abuse in drug abusers. Gonadal hormones appear to play a critical role in the altered approach/avoidance behavior observed when repeated cocaine is used as the environmental stimulus (see text).

Evolutionary Theory
Newlin has proposed that many of these same functions, such as stimulus salience, motivated approach/avoidance, and attention, are directly relevant to the survival and reproduction of the rodent. Therefore, evolutionary theory may be particularly helpful in understanding these behaviors. Newlin has argued that the mesocorticolimbic dopamine system (and its many modulating influences) has evolved to control survival and reproductive behavior. Rather than being merely a "reward center" or even "reward pathway", this system advances survival functioning in the face of both appetitive (such as drugs of abuse) and aversive stimuli (such as Form). Specifically, affective hedonics (such as reward or disgust) are much less important to the animal than are survival and reproductive functions. Therefore, sensitization may reflect amplification of survival and reproductive motivation; following repeated exposures to cocaine or to Form, the animal expresses amplified survival functioning.

In humans, the construct of SPFit (self-perceived survival ability and reproductive fitness) describes the inherent capacity of humans to conceptualize and self-perceive their "fitness" (in an evolutionary sense). SPFit is highly adaptable and is strongly influenced by cultural and psychological factors, but reflects the operation of survival and reproductive motivation that is controlled by mesolimbic structures. In this model, the drug abuser is attempting to artificially enhance his/her SPFit by taking drugs of abuse, and the MCS patient is seeking to protect SPFit by avoiding environmental chemicals. In MCS, environmental chemicals, even at very low levels, are perceived as serious threats to survival (or to SPFit). This threat is magnified by prior exposure and the resulting sensitization of mesolimbic circuitry, leading to extreme defensive behavior that we label clinically as MCS.

Summary
These studies indicate in experimental animals that repeated exposure to a relatively low-level volatile organic compound, Form, produces amplified behavioral responses that are at least partially dependent upon sensitization of the mesocorticolimbic dopamine system, and possibly other brain areas that send projection neurons to these dopaminergic regions. The implication is that the circuitry shown in Fig. 1 underlies motivational aspects of responses to environmental stimuli, translating these stimuli into behavioral output. Amplified behavioral responses may be a consequence of the inescapable nature of Form exposures, which may be different from the situation in humans, who are able to escape situations of chemical exposures. However, in both avoidable and unavoidable chemical exposures, activation of the stress axis may occur. Therefore, the results from the animal studies may be extrapolated to humans, at least for the purposes of determining whether there is predictive validity regarding therapeutic strategies that could reverse or block the consequences of repeated stress axis activation.

Evolutionary theory in the context of MCS suggests that the perception of threat, as opposed to the adverse consequences of the chemical itself, may be just as important from a physiological and behavioral standpoint. In humans, this perception of threat may be controlled by SPFit, a psychological structure concerning biological fitness that has roots in the mesocorticolimbic dopamine system.

Contact: Barbara A. Sorg, Alcohol and Drug Abuse Program and Program in Neuroscience, Department of VCPP. Washington State University, Pullman, WA 99164-6520, USA.

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